Depression is one of the most common mental illnesses. However, the pathogenesis and underlying neurobiology of depression remain poorly understood and not all depressed patients respond to current available treatments. Our recent studies have identified a role for leptin a hormone secreted from adipose tissue, in emotional processes and demonstrated that leptin has the potential as a novel antidepressant. The goal of this project is to elucidate the neural mechanisms underlying the antidepressant-like effects of leptin. First, we plan to investigate the potential role of leptin in hippocampal neurogenesis. Second, the importance of leptin action on the hippocampus in emotional behaviors will be addressed using both pharmacological and genetic approaches. Third, we will investigate the functional interaction between leptin and the serotonergic system. Our main hypothesis is that leptin's antidepressant-like activity is mediated by specific brain circuits and neurotransmitters. These studies will contribute to mechanistic understanding of the role of leptin in depression and provide insights into novel therapeutic approaches for the treatment of depressive disorders.